Development of New N,N-Ligands for the Enantioselective Copper(II)-Catalyzed Henry Reaction

Abstract

This account shows our efforts towards the development of new N,N-ligands and their application in the asymmetric Henry reaction. Iminopyridine ligands were prepared by the condensation of chiral monoterpene ketones and pyridinylalkylamines. The complexes of these ligands with copper(II) ions catalyzed the enantioselective addition of nitromethane to aldehydes with generally high yields and moderate enantioselectivities. The same reaction with other nitroalkanes gave racemic products. Stereoselective reduction of the imino group allowed us to obtain new aminopyridine ligands. The new ligands were shown to be more efficient, and they catalyzed the addition of nitromethane and also larger nitroalkanes to aldehydes to give the corresponding products in generally very high yields and excellent enantiomeric excesses. We have used this aminopyridine catalytic system in the first catalytic enantioselective Henry reactions with bromo(nitro)methane and methyl 4-nitrobutanoate. The reaction involving the latter substrate gave multifunctional chiral building blocks that were transformed into g-lactams and d-lactones. The application of the reaction to the synthesis of known amino(aryl)ethanol pharmaceuticals is also reported. Iminopyridine ligands, however, were more efficient in the addition of nitromethane to a-keto esters.

Enantioselective copper‐aminopyridine‐catalyzed aza‐Henry reaction with chelating N‐(2‐pyridyl)sulfonyl imines

“…With respect to the stereochemical mechanism, the results indicate a preference for the nitronate to attack from the Si face of the C═N double bond. According to our previous studies on the Henry reaction, we propose a plausible stereochemical model that would account for the observed stereochemistry (Fig. ).…”

“…Our group has developed new iminopyridine and aminopyridine ligands (Fig. ), which in the presence of copper(II) salts catalyzed the Henry reaction with carbonyl compounds very efficiently and with very high enantioselectivity . In this article, we describe the application of these catalysts in the enantioselective aza‐Henry reaction with N ‐(2‐pyridyl)sulfonyl aldimines.…”

Asymmetric Henry Reaction of 2-Acylpyridine N-Oxides Catalyzed by a Ni-Aminophenol Sulfonamide Complex: An Unexpected Mononuclear Catalyst

“…The asymmetric construction of chiral quaternary stereocenters represents a considerable challenge in modern organic synthesis [1,2,3,4,5,6]. The Henry (nitroaldol) reaction [7,8,9,10,11,12,13] of ketones has become one of the most important and versatile reactions for the construction of quaternary carbons containing hydroxyl and nitro groups. In recent years, considerable effort has been devoted to the development of efficient chiral catalysts for asymmetric Henry reactions of reactive ketones, such as trifluoromethyl ketones (for selected examples, see ref [14,15,16,17,18]), α-keto esters (for selected examples, see [19,20,21,22,23,24]), α-keto amides (for selected examples, see [25,26]), α-keto-phosphonates [27,28], and glyoxal hydrates [29].…”

Silver comes into play: Henry reaction and domino cycloisomerisation sequence catalysed by [Ag(i)(Pc-L)] complexes

“…[8][9][10] No need for a stoichiometric amount of a base, metal-catalysts, 11-15 enzymes 16,17 or organocatalysts [18][19][20] can efficiently promote the Henry reaction. Among the metal complexes commonly employed as catalysts, copper(I) [21][22][23][24][25][26][27][28][29][30] and copper(II) 11,[31][32][33][34][35][36][37][38][39][40][41][42][43][44] complexes play a prominent role, whereas, to the best of our knowledge the activity of silver salts and complexes have rarely been tested. In several cases reported in the literature, the replacement of Cu with Zn gave comparable results but in some of them a reversed enantioselectivity was observed.…”